The long term goal of this research program is the development of methods for robust and accurate prediction of protein structures to high resolution, starting from the amino acid sequence, as well as enumeration of low energy alternative conformations of protein active sites. Achievement of these objectives would enable structure based drug design methods to be effectively applied to a much wider range of targets, via homology modeling, than is currently feasible; it would also enable pharmaceutically interesting ligands to be designed to fit into the alternative conformations elucidated by the computations. To accomplish these goals, it is essential to develop improved molecular mechanics force fields, models for aqueous solvation, and sampling algorithms capable of searching phase space with both speed and acceptable accuracy. Novel efforts in each of these areas are proposed, as well as the development of an integrated protein modeling package which will enable the technology to be used by others in the biomedical community. Extensive benchmarking of various models and computational methods against experimental data will be performed, in some cases in collaboration with other leading researchers. Specific biological applications of the methods will involve homology modeling of pharmaceutically interesting targets, such as kinases. [unreadable] [unreadable]